1. Field of the Invention
The fifty percent increase in life expectancy of Americans from 1930 to 1980 can, in part, be attributed to the improvement in nutrition in the United States during that period. However, the situation today remains far from ideal, since six out of ten of the leading causes of death in this county, including heart attack, cancer, cirrhosis of the liver, and diabetes, are linked to diet. It becomes increasingly obvious that many of those diseases could be prevented with a well balanced diet and efficient nutritional supplementation with certain vitamins and minerals.
The problem is particularly severe in older Americans. Approximately 30 percent of older Americans do not get the dietary requirements of all the essential nutrients. The hazards of food-drug interactions in depleting essential nutrients are well recognized. It is unavoidable that old age calls for increased use of medications. For example, use of certain antibiotics decreases absorption of calcium and iron, while EDTA chelation therapy decreases absorption of zinc, iron, copper, and magnesium.
In addition, many foods which increase the risk of cancer and cardiovascular disease have to be eliminated from the diet, which further depletes the sources of essential nutrients. For example, excellent sources of vitamin B and vitamin D, such as red meat, liver, egg yolk, cheese and dairy products, have to be limited because of their high cholesterol content.
Limited menu also causes a depletion of essential amino acids, such as tryptophan which is important precursor of neurotransmitters and may play a role in the prevention of brain deterioration with aging.
The availability of essential nutrients is further compromised by poor gastrointestinal absorption.
The traditional way to offset insufficient nutrient supplementation, insufficient gastrointestinal absorption and insufficient metabolic utilization of essential nutrients is to administer large doses of, e.g., vitamin and mineral supplements.
2. Description of Related Art
Documents describing ayurvedic medicine dating from the period between the seventh century B.C. and the sixth century A.D. describe "trikatu". Trikatu is a sanskrit word meaning three acrids, and refers to a combination of black pepper (Piper nigrum Linn.), long pepper (Piper longum Linn.) and ginger (Zingiber officinale Rosc.). In traditional ayurvedic medicine these drugs are essential ingredients of many prescriptions and formulations used for a wide range of diseases. Experimental evidence shows that the use of "trikatu", and its constituents individually as well as collectively, enhance the bioavailability of a number of drugs. In those studies carried out in animals as well as human volunteers, it was noted that the active component is piperine. Piperine, or mixtures containing piperine, have been shown to increase the efficacy, blood levels, and bioavailability of a number of drugs including ingredients of vasaka leaves (Bose, K. G., (1928) Pharmacopeia India, Bose Laboratories, Calcutta), vasicine (Atal et al., Journal of Ethnopharmacology, 4, 229-233 (1981)), spartein (Atal et al., ibid), sulfadiazine (Atal et al., ibid), rifampicin (Zutshi, U. et al. (1984) Journal of the Association of Physicians of India, 33, 223-224), phenytoin (Bano et al., Planta Medica, 1987, pp. 568-569), pentobarbitone (Majumdar, A. N. et al. (1990), Indian Journal of Experimental Biology, 28, 486-487), theophylline (Bano et al., Eur. J. Clin. Pharmacol. (1991) 41:615-617) and propranolol (ibid).
Piperine has also been added in multi-drug formulations for the treatment of tuberculosis and leprosy. A formulation containing rifampicin, pyrazinamide and isoniazid has been tested in human volunteers (Indian Patent No. 1232/DEL/89). For most drugs, the comparative levels and peak concentration of the drugs in the presence of piperine were higher. The applicability of these results to the development of anti-tuberculosis and anti-leprosy formulations, which are presently cost prohibitive in developing countries, is apparent. Bioavailability enhancement helps to lower dosage levels and shorten the treatment course.
The effect of piperine on the bioavailability of propranolol has also been studied. The chronic oral administration of the anti-hypertensive agent propranolol is frequently rendered difficult due to the fact that steady therapeutic levels of this drug are not achieved or maintained. In addition, large doses are needed to be administered for efficacy and this frequently causes side-effects. Piperine has been shown to enhance the bioavailability of this drug. Propranolol administered with piperine shows a significant increase in plasma levels of the drug, presumably due to decrease in metabolism by the liver.
Similar results have been obtained with piperine and vasicine, theophylline, and phenytoin. In summary, all of these examples clearly illustrate the role of piperine as a drug bioavailability enhancer. The combination of piperine with tested drugs is effective primarily due to higher plasma concentration and a longer stay of the drugs in the body. The reduced dose of highly toxic drugs and their enhanced efficacy is obviously desirable.
As noted above, the exact mechanism of drug bioavailability enhancement by piperine is unknown. Several studies indicate that piperine may act primarily by non-specifically inhibiting the mixed function oxidases systems. This slows down the process of metabolic biodegradation of the drug and enhances the bioavailability of the drug. In a detailed study of the interaction of piperine with enzymatic drug biotransforming reactions in jejunal epithelial cells and liver hepatocytes in vitro and in vivo, piperine appears to be a non-specific inhibitor of drug metabolism. Such results led the authors to speculate that piperine may find useful applications in successful drug therapy, and represent an important addition to the chemotherapists armory for the quantitative enhancement of drug bioavailability (Atal et al., The Journal of Pharmacology and Experimental Therapeutics, Vol. 232, pp. 258-262, 1985).